Most drugs are not amenable to transdermal mode of administration due to the well-known barrier properties of the skin. Molecules moving from the environment into and through intact skin must first penetrate the stratum-corneum. It is the stratum-corneum that presents the greatest barrier to absorption of topical compositions or transdermally administered drugs. The stratum-corneum, the outer horny layer of the skin, is a complex structure of compact keratinized cell remnants separated by lipid domains. Compared to the oral or gastric mucous, the stratum-corneum is much less permeable to outside molecules.
The flux of a drug across the skin can be increased by changing either a) the resistance (the diffusion coefficient), or b) the driving force (the solubility of the drug in the stratum-corneum and consequently the gradient for diffusion). Many enhancer compositions have been developed to change one or more of these factors, and are known in the art. U.S. Pat. Nos. 4,006,218, 3,551,154 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of topically applied drugs through the stratum corneum. Combinations of enhancers consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermal delivery of steroids such as progestogens and estrogens. A dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720. U.S. Pat. No. 5,006,342 lists numerous enhancers for transdermal drug administration consisting of fatty acid esters or fatty alcohol ethers of C.sub.2 to C.sub.4 alkanediols, where each fatty acid/alcohol portion of the ester/ether is of about 8 to 22 carbon atoms. U.S. Pat. No. 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C.sub.2 or C.sub.3 alkanol and an inert diluents such as water.
The use of sorbitan esters of long chain aliphatic acids as skin permeation enhancers is disclosed in U.S. Pat. Nos. 5,122,383; 5,212,199 and 5,227,169. Skin permeation enhancement using aliphatic alcohol esters of lactic acid is disclosed in U.S. Pat. No. 5,154,122, World Patent 95/09006 and in Dohi et al., Enhancing Effects of Myristyl Lactate and Lauryl Lactate on Percutaneous Absorption of Indomethacin, Chem Pharm. Bull. 38 (October 1990) 2877-2879. U.S. Pat. No. 5,314,694 also makes reference to the use of esters of fatty acid alcohols, i.e. lauryl alcohol and lactic acid as a permeation enhancer component.
World Patent 96/37231 teaches the use of acyl lactylates as permeation enhancers for drug delivery purposes. This patent is specific to esters of fatty acids and lactic acid such as caproyl lactylic acid and lauroyl lactylic acid. It is stated that the salt form of acyl lactylates are not effective as permeation enhancers.
Many of the enhancer systems possess negative side effects such as toxicity, skin irritation and incompatibility with the drugs or other ingredients making up the transdermal system. U.S. Pat. No. 4,855,294 discloses compositions for reducing skin irritation caused by drug/enhancer compositions having skin irritation properties comprising a percutaneously absorbable drug, a binary enhancer composition consisting of a solvent and a cell envelope disordering compound, combined with an amount of glycerin sufficient to provide an anti-irritating effect.
Skin permeation enhancement due to fatty acid sucrose esters is disclosed in U.S. Pat. No. 4,940,586. Penetration enhancement resulting from combining free base and acid addition salt combinations of drugs is taught in U.S. Pat. No. 4,888,354. Enhancement of drugs by means of sub-saturation in a carrier is disclosed in U.S. Pat. No. 5,164,190.
U.S. Pat. Nos. 6,066,328 and 5,658,575 “Cosmetic or dermatological composition comprising an oil-in-water emulsion based on oily globules provided with a lamellar liquid crystal coating and made of—at least one lipophilic surface-active agent, at least one hydrophilic surface-active agent, and at least one fatty acid, the coated oily globules having a mean diameter of less than 500 nanometermeters, preferably less than 200 nanometermeters, and the oily phase contains a basic agent in the dissolved state, exhibit good skin and hair penetration”
U.S. Pat. No. 6,004,566 disclose oil-in-water sub micron emulsions that enhance absorption due reduction of mean particles size to below half a micron. However, two components are needed for stabilizing the emulsion, an emulsifying stabilizer and a surfactant.
All patents, mentioned above, do not disclose oil-in-glycerin type composition or homogenized oil-in-glycerin emulsions stabilized with fatty acid/s and carbohydrate conjugates. Many of the enhancer chemicals listed above were not exploited due to dose dependent skin adverse reaction that limits their clinical use. Alcohols, azones, fatty acids such as oleic acid and other suggested skin permeation enhancers are also causing skin damage or irritation or sensitization.
Oil-in-glycerin emulsions have been claimed in PCT/IL00/00142. Said specification describes a composition of matter comprising a stable oil-in-glycerin emulsion containing at least one oil, at least one emulsifying stabilizer and glycerin. Said invention relates to oil-in-glycerin emulsions in which the oil is the internal phase and the glycerin is the external, continuous phase. However, this patent do not refers to the unexpected observation of facilitated stratum-corneum penetration and method of intra-dermal and transdermal medication which involves the transport of drugs or cosmetics active agent into and/or through the skin.
It would be desirable to have an enhancer composition which not only enabled the passage of drug compositions across the skin barrier but which was also beneficial to the moisturization, stability and overall vitality of the epidermis. Skin having properly moisturized stratum corneum is smooth to the touch, flexible and elastic due to the presence of sufficient bound water. A 1% variation of water content may be enough to modify skin elasticity and permeability. Suitable skin hydration-also promotes transdermal delivery of drugs through the stratum corneum.
To be considered useful, a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of agents. More importantly, it should be able to enhance the skin permeability such that the agent delivery rate from a reasonably sized system (preferably 5-50 cm.sup.2) is at therapeutic levels. Additionally, the enhancer when applied to the skin surface should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably, it should be odorless and capable of delivering agents without producing burning or tingling sensations.
It is the objective of the present invention to furnish a carrier system for bioactive agents comprising at least one hydrophobic moiety, whereas an enhanced absorption is obtained while avoiding the side effects associated with many of the chemical enhancers such as alcohols or sodium lauryl sulfate and also provide for safe and biodegradable product and also free of synthetic polymers and also free of preservatives.
The advent of genetic engineering and especially recombinant DNA technology has made available many biologically active peptides. The peptides include human insulin, human growth hormone, bovine growth hormone, endorphins and enkephalines, calcitonin, interferons, interleukins and other lymphokines, TPA, vasopressin, oxytocin and many others.
Peptides are made up of groups of amino acid linked together by amide bonds. The distinction between peptides and proteins, which also are groups of amino acids linked by amide bonds, is somewhat vague, but usually they are separated by size or number of amino acids in the chain.
Use of these biologically active peptides in medical practice is not so simple. Because of the nature of the peptide bond, they are not stable in the acidic conditions of the stomach and thus have very poor oral activity. The most common route of administering biologically active peptides is by injection by the intravenous or I.M. or S.C. routes, which are not amenable to outpatient treatment.
In addition to the acid instability of peptides, enzymes in the body known as peptidases break down these peptides, rapidly destroying their biological activity, some peptides, e.g., Angiotensin I and bradykinin, have a half-life of less than 30 seconds. A transdermal delivery system for peptides would be ideal in many ways.
Unexpectedly, it has now been discovered that bioactive agents having at least one hydrophobic moiety such as phytomedicine, peptides, drugs and cosmeceuticals formulated in homogenized oil in glycerin permeation enhancer compositions of mean droplet size of below one micron better penetrate the stratum corneum natural protective layer of the skin and show higher dermal concentration and/or biological dermal effect. Bioactive agents that will not be biodegraded in the dermis and that will accumulate in the dermis, will finally diffuse into the circulation and will result in systemic effect via transdermal route.